NORD gratefully acknowledges A. Simon, MD, PhD Radboud University Medical Centre, Department of Internal Medicine, Nijmegen, The Netherlands and the Radboudumc Expertise Centre for Immunodeficiency and Autoinflammation (REIA), for assistance in the preparation of this report.
Schnitzler syndrome is a rare disorder characterized by a chronic reddish rash that resembles hives (urticaria) and elevated levels of a specific protein in the blood (monoclonal IgM gammopathy). Symptoms associated with Schnitzler syndrome may include repeated bouts of fever, joint inflammation (arthritis), joint pain (arthralgia), bone pain, and other findings such as enlarged lymph nodes (lymphadenopathy). A monoclonal IgM gammopathy refers to the uncontrolled growth of a single clone (monoclonal) of plasma cells, which results in the abnormal accumulation of M-proteins (also known as immunoglobulin M or IgM) in the blood. However, the specific role these proteins play and the exact cause of Schnitzler syndrome is unknown. Schnitzler syndrome is difficult to classify and some researchers have suggested that it is an acquired autoinflammatory syndrome. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. They are not the same as autoimmune disorders, in which the adaptive immune system malfunctions and mistakenly attacks healthy tissue.
The symptoms associated with Schnitzler syndrome can vary from one person to another. The symptoms can occur all at once or, because they often come and go, the symptoms can occur at different times. The symptoms tend to persist for many years (chronic disease).
A reddish, rash that resembles hives (urticaria) is the hallmark finding associated with Schnitzler syndrome. The distinctive rash usually consists of raised, reddish bumps (papules) and flatter, wider lesions (plaques). In most cases, a rash is the first symptom to appear in individuals with Schnitzler syndrome. The rash usually lasts for a day to two and then disappears without scarring. However, a new rash often develops each day so that a rash is a constant occurrence but the frequency of the rash can vary greatly from one person to another and some people only develop a rash a few times during the year.
When the rash first develops, it usually is not itchy (not pruritic). However, in approximately 45 percent of cases, the rash will become itchy within a few years. The trunk, arms and legs are most often affected. The head, neck, palms and soles are usually spared. Some affected individuals have reported that alcohol, spicy foods and stress have aggravated the rash.
Fevers that come and go over a period of time (chronic, intermittent fevers) are the second most common symptom in individuals with Schnitzler syndrome. The frequency of fevers varies greatly, ranging from being a daily occurrence to only a couple times per year. Fevers are usually unrelated to the skin rash, are well-tolerated and are rarely accompanied by chills.
Additional symptoms associated with Schnitzler syndrome include bone pain, most often affecting the lower legs and hips, and joint pain, most often affecting the large joints such as the hips, knees, wrists and ankles. In some cases, inflammation of the joints (arthritis) may develop with accompanying swelling, redness and a feeling of heat or warmth in the joint. Despite joint involvement, joint degeneration or destruction has not been reported in individuals with Schnitzler syndrome.
Abnormal enlargement of the lymph nodes (lymphadenopathy), the liver (hepatomegaly) and the spleen (splenomegaly) may also occur in some cases. Additional nonspecific symptoms that have been reported in individuals with Schnitzler syndrome include unintended weight loss, fatigue and a general feeling of poor health (malaise). Rapid swelling due to fluid accumulation just beneath the surface skin (angioedema) is very rare.
Most cases of Schnitzler syndrome have a chronic, benign course. However, over a period of 10 years, approximately 15 percent of affected individuals developed cancer, most often cancer caused by the overproduction of white blood cells (lymphoproliferative disorders) such as Waldenström macroglobulinemia.
Some individuals with Schnitzler syndrome have elevated levels of a different protein (see Causes section below) than individuals with classic Schnitzler syndrome. These individuals are classified as having variant Schnitzler syndrome and have very similar symptoms to classic Schnitzler syndrome.
The exact cause of Schnitzler syndrome is unknown. Researchers believe that specific parts of the immune system may not function properly, eventually causing Schnitzler syndrome.
Individuals with Schnitzler syndrome also have a clinical finding called monoclonal IgM gammopathy, in which abnormalities affecting the production of immunoglobulins result in elevated levels of a specific immunoglobulin M (IgM) in the body. Immunoglobulins are proteins produced by certain white blood cells. There are five classes of immunoglobulins known as IgA, IgD, IgE, IgG, and IgM. Immunoglobulins play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells.
At the time of diagnosis, IgM levels may only be slightly elevated and may remain stable for years.
A variant form of Schnitzler syndrome has been reported in which individuals have a monoclonal gammopathy of IgG instead of IgM.
Certain cytokines (specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells) play a role in the development of Schnitzler syndrome. The cytokine interleukin-1 (IL-1), is an important mediator of the inflammation in Schnitzler syndrome. Abnormal clinical findings involving interleukin-1 have been found in some individuals with Schnitzler syndrome and therapy with drugs that block the activity of interleukin-1 have brought about complete remission (see Investigational Therapies below).
Schnitzler syndrome affects males slightly more often than females. However, only approximately 160 cases of this rare disorder have been reported in the medical literature so no definitive conclusions can be made about ethnic or gender predispositions. Because of the varied symptoms and rarity of Schnitzler syndrome, a diagnosis is usually delayed by several years and researchers believe that the disorder is underdiagnosed, making it difficult to determine its true frequency in the general population. Most individuals with Schnitzler syndrome are in their 50s when the characteristic symptoms develop.
Less often, symptoms have been noted in individuals in their 30s. In one reported case, symptoms were identified in an individual 12 years old. It is to be questioned whether these cases were classical Schnitzler syndrome (see Related Disorders below).
Schnitzler syndrome was first described in the medical literature in 1972, by a French dermatologist named Liliane Schnitzler. Most of the reported cases of Schnitzler syndrome have been from Europe, particularly France, but cases from Australia, Japan and the United States have been reported too.
A diagnosis of Schnitzler syndrome is based upon a thorough clinical evaluation, a detailed patient history, exclusion of other disorders, and identification of characteristic findings, specifically a urticarial rash, an M protein and at least two of the following findings – fever, joint pain or inflammation, bone pain, palpable lymph nodes, enlargement of the liver or spleen, elevated numbers of white blood cells (leukocytosis), elevated red blood cell (erythrocyte) sedimentation rate or abnormalities on bone morphological study, which can reveal increased bone density (osteosclerosis).
Sedimentation rate measures how long it takes red blood cells to settle in a test tube over a given period. Many individuals with Schnitzler syndrome have an elevated sedimentation rate, which is an indication of inflammation.
In younger patients, careful attention should be paid because alternative diagnosis is much more likely and often overlooked – such as urticarial vasculitis, hematological disease or chronic idiopathic urticaria – which needs a different approach to treatment – so a diagnosis of Schnitzler’s syndrome in younger patients should only be made after extensive work on exclusion of other diagnoses.
First-line treatment in mild cases is with nonsteroidal anti-inflammatory drugs (NSAIDs). But this is often not sufficient.
In more severe cases, the standard treatment is with therapy to inhibit the cytokine IL-1. Patients with Schnitzler syndrome are successfully treated with anakinra, an interleukin-1 receptor antagonist. Anakinra is a drug that blocks the activity of interleukin-1, which some researchers believe plays a key role in the development of Schnitzler syndrome. There have also been at least 2 studies showing the efficacy of the interleukin-1 beta antibody canakinumab.
High-dose regimens of corticosteroids have temporarily improved symptoms in some cases, but usually must be stopped due to side effects. In a small percentage of cases, colchicine (a medication used to suppress inflammation in acute gout) and dapsone were effective in treating some individuals with Schnitzler syndrome. Interleukin-6 is a cytokine that can be induced by interleukin-1; , anti-interleukin-6 therapy was also recently tried in three patients with Schnitzler syndrome, in which it was effective.
At least three individuals with Schnitzler syndrome have been successfully treated with thalidomide, a drug that affects how the immune system works (immunomodulatory drugs). Thalidomide induced a complete resolution of the rash and dramatic improvement of other symptoms in three individuals who received the drug as a therapy for Schnitzler syndrome. However, thalidomide is often associated with significant side effects including pain, numbness and a tingling sensation in the hands and feet (peripheral neuropathy). Two of the three patients had to stop thalidomide therapy because of side effects. In addition, two additional individuals with Schnitzler syndrome did not improve after treatment with thalidomide. More research is necessary to determine the long-term safety, effectiveness and role, if any, of thalidomide in treating individuals with Schnitzler syndrome.
A small study investigated the effectiveness of the antibiotic drug, pefloxacine, for the treatment of Schnitzler syndrome. Eleven affected individuals received pefloxacine, which caused rapid and dramatic improvement of both the rash and systemic symptoms associated with the disorder. More research is necessary to determine the long-term safety and effectiveness of pefloxacine in the treatment of individuals with Schnitzler syndrome.
Schnitzler syndrome does not affect lifespan in most cases, but requires periodic follow up because of the increased risk of developing cancer.
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Researchers in the department of General Internal Medicine at the Radboud University Medical Center Nijmegen, The Netherlands, have created a website to provide information and support for individuals with Schnitzler syndrome. The researchers have an active interest in this rare disorder and have started an international registry on Schnitzler syndrome. The registry is a database that catalogues information on affected individuals to increase knowledge of this disorder. The Web site is located at: http://www.autoinflammatie.nl/ENG/folder9/index.php
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